The role of hypothalamic peptide hormones with special emphasis on the melanotropin release inhibiting factor and thyrotropin releasing hormone, in the regulation of acute (analgesia hypothermia, catalepsy, etc.) and chronic effects (tolerance and physical dependence) of opiates will be investigated. In addition to the naturally occurring hormones, which have short biological half life, studies will be carried out with their synthetic analogs. The opiates will include endogenous (endorphins) and exogenous (morphine type (agonists) and buprenorphine, butorphanol etc., (agonist-antagonist type)) opiates. Tolerance and physical dependence on morphine type analgesics will be produced by pellet implantation procedure, whereas, the endorphins will be injected via indwelling cannulae in the brain. Tolerance will be assessed by measuring the analgesic, hypothermic, cataleptic and locomotor activity to a challenge dose of an opiate in tolerant and non-tolerant mice and rats. The degree of physical dependence will be assessed by measuring the intensity of hypothermic response, body weight loss observed during abrupt and antagonist induced withdrawal and also the intensity of stereotyped jumping syndrome seen after precipitated withdrawal. Our study indicated that it is possible to block tolerance to narcotic drugs with the hypothalamic hormones. When used concomitantly with opiates to relieve pain, these peptide hormones or their synthetic analogs may prove to be useful in therapy.